PARANEOPLASTIC MANIFESTATIONS OF LUNG CANCER
Paraneoplastic effects of tumors are remote effects that are not related to direct invasion, obstruction, or metastases. Paraneoplastic syndromes occur in 10% to 15% of all lung cancers. The following are some of the most common.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may be caused by pulmonary infections, central nervous system (CNS) disease or trauma, drugs, or lung tumors. Small cell lung cancer is the most common malignancy to cause SIADH. The tumor secretes ectopic antidiuretic hormone (ADH; vasopressin), which exerts its action on the kidneys and enhances the ﬂow of water from the lumen of the renal collecting ducts to the medullary interstitium with resulting concentration of the urine. Patients present with hyponatremia that is associated with low plasma osmolality and elevated urine sodium and osmolality. To make the diagnosis of SIADH, patients must also have normal renal, adrenal, and thyroid function. The symptoms of hyponatremia may include anorexia, nausea, vomiting, irritability, restlessness, confusion, coma, or seizures. The severity of symptoms is related to the degree of hyponatremia and the rapidity of the decrease in serum sodium. The treatment for mildly symptomatic patients is to restrict ﬂuid intake to 500 to 1000 mL/24 hours. For more severe or life-threatening symptoms, treatment consists of intravenous ﬂuids with normal saline and loop diuretics. For severe symptoms, some experts recommend 300 mL of 3% saline intra-venously, but extreme caution must be used because too rapid correction of serum sodium may be associated with central pontine myelinolysis, which is a devastating CNS process that is often fatal. For patients with less severe symptoms from hyponatremia but requiring more than ﬂuid restriction, oral demeclocycline can be used. The onset of action may take from a few hours to a few weeks, and renal function should be monitored. The best treatment for SIADH, if the patient is stable, is to treat the small cell lung cancer with systemic chemotherapy. Regression of the tumor results in nor- malization of the sodium in most cases.
Cushing syndrome may be related to ectopic production of corticotropin (adrenocorticotropic hormone) or corticotropin-releasing hormone by small cell carcinoma. It has also been reported with bronchial carcinoid tumors or carcinoid tumors of the thymus or pancreas. Small cell lung cancer accounts for 75% of all cases of Cushing syndrome caused by ectopic hormone secretion. Because of the rapid growth of small cell lung cancer, patients are more likely to present with edema, hypertension, and hyperglycemia with or without muscle weakness. This is in contrast to the classic features of Cushing syndrome that include truncal obesity, rounded (moon) facies, buffalo hump (dorsocervical fat pad), and diabetes mellitus. The best screen for Cushing syndrome caused by ectopic hormone secretion is the 24-hour urine free cortisol measurement. Marked elevation of cortisol production and plasma corticotropin levels are highly suggestive of ectopic corticotropin as the cause of Cushing syndrome.
Treatment of patients with ectopic corticotropin production includes metyrapone, aminoglutethimide, mitotane, or ketoconazole given alone or in combination. Ketoconazole is the most commonly used agent. If the patient is stable with no superimposed infection, then systemic chemotherapy is the best treatment for histologically conﬁrmed small cell lung cancer. If the Cushing syndrome is caused by carcinoid tumor, then surgical resection, if possible, is the treatment of choice. Hypercalcemia in relation to lung cancer may be caused by bone metastases, or less commonly, secretion of parathyroid hormone–related protein (PTHrP) or other cytokines. The most common cancers to cause paraneoplastic hypercalcemia are kidney, lung, breast, myeloma, and lymphoma. For lung cancers, squamous cell carcinoma is the most common cell type associated with hypercalcemia. Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, lethargy, polyuria, polydipsia, and dehydration. Confusion and coma are late manifestations. A shortened QT interval on electrocardiography, ventricular arrhythmia, heart block, and asystole may occur. Renal failure and nephrocalcinosis are also possible. Elevated PTHrP levels may be detected in the serum of about half of patients with hypercalcemia of malignancy that is not caused by bony metastasis. Patients with mild elevation of calcium do not require treatment. Treatment is determined by symptoms and includes intravenous ﬂuids to correct dehydration caused by polyuria and vomiting. Intravenous treatment with bisphosphonates inhibits osteoclast activity, and one dose achieves a normal calcium level in 4 to 10 days in most individuals. If rapid partial correction of hypercalcemia is needed, calcitonin will rapidly lower the calcium level by 1 to 2 mg/dL, but the effects are short lived. If the lung cancer is localized, then the treatment of choice, after the patient has been stabilized, is surgical resection. However, the usual situation is that the patient has metastatic disease. For these individuals with hypercalcemia, the average life expectancy, even with treatment, is 1 month.
Paraneoplastic neurologic syndromes (PNSs) are most commonly associated with small cell lung cancer and are quite variable. They include Lambert-Eaton myasthenic syndrome (LEMS), sensory neuropathy, encephalomyelopathy, cerebellar degeneration, autonomic neuropathy, retinal degeneration, and opsoclonus. Limbic encephalitis (dementia with or without seizures) has frequently been observed. The neurologic syndromes may precede the diagnosis of lung cancer by months to years.
PNSs are thought to be immune mediated on the basis of identifying autoantibodies. The antineuronal nuclear antibody (ANNA-1), also known as anti-Hu antibody, has been associated with small cell carcinoma and various neurologic syndromes. ANNA-2 (anti-Ri antibody) and CRMP-5 antibody have also been associated with various PNSs. These antibodies predict the patients’ neoplasm but not a speciﬁc neurologic syndrome. The ANNA-1 binds to the nucleus of all neurons in the central and peripheral nervous system, including the sensory and autonomic ganglia and myenteric plexus.
Proximal muscle weakness, hyporeﬂexia, and autonomic dysfunction characterize LEMS. Cranial nerve involvement may be present and does not differentiate LEMS from myasthenia gravis. There is a strong association of LEMS with antibodies against P/Q type presynaptic voltage-gated calcium channels of the peripheral cholinergic nerve terminals. These antibodies have also been identiﬁed in 25% of patients with small cell lung cancers with no neurologic syndrome. Myasthenia gravis, in contrast to LEMS, is associated with antiacetylcholine receptor antibodies. Malignancy is identiﬁed in approximately 50% of patients with LEMS, and small cell lung cancer is by far the most common type. The diagnosis of LEMS is based on the characteristic electromyographic (EMG) ﬁnding that shows a small amplitude of the resting compound muscle action potential and facilitation with rapid, repetitive, and supramaximal nerve stimulation. A single-ﬁber EMG is optimal for making the diagnosis. Careful radiographic evaluation of the lungs and mediastinum is indicated, especially in current or former smokers who have a suspected PNS. In many cases, the radiographic ﬁndings are very subtle. If the patient has a positive paraneoplastic autoantibody blood test result and the computed tomography (CT) chest scan does not reveal an abnormality, then current guidelines recommend that a positron emission computed tomography (PET) scan be performed to look for an occult malignancy. Strong consideration should be given to biopsy of even subtle abnormalities because without diagnosis and treatment the PNS will progress, frequently with devastating consequences.
The best treatment for patients with PNS caused by small cell lung cancer is to treat with chemotherapy with or without thoracic radiotherapy, depending on the stage of disease. LEMS may improve with treatment, but not always. The other PNSs rarely improve with treatment, but the goal is to treat the lung cancer as soon as possible to try to prevent progressive neurologic disease.
Skeletal muscular paraneoplastic syndromes include digital clubbing, hypertrophic pulmonary osteoarthropathy (HPO), and dermatomyositis or polymyositis. Clubbing may involve the ﬁngers and toes and consist of selective enlargement of the connective tissue in the terminal phalanges with loss of the angle between the base of the nail bed and cuticle, rounded nails, and enlarged ﬁngertips. There are nonmalignant causes of clubbing such as pulmonary ﬁbrosis or congenital heart disease. HPO is uncommon in association with lung cancer and is characterized by painful joints that usually involve the ankles, knees, wrists, and elbows and is most often symmetric. Some patients may complain of pain or tenderness along the shins. The pain and arthropathy is caused by a proliferative periostitis that involves the long bones but may involve metacarpal, metatarsal, and phalangeal bones. Clubbing may be present along with HPO. Large cell and adenocarcinoma are the most common types to cause HPO. The cause of HPO is uncertain but is thought to be attributable to a humeral agent. A radiograph of the long bones (tibia and ﬁbula or radius and ulna) may show the characteristic periosteal new bone formation. An isotype bone scan or PET scan typically demonstrates diffuse uptake in the long bones. Symptoms of HPO may resolve with thoracotomy with or without resection of the malignancy. For inoperable patients, treatment with nonsteroidal anti-inﬂammatory agents is often of beneﬁt. Recently, the use of intravenous bisphosphonates has been reported to alleviate the symptoms of HPO.
There have been reports of the association of lung cancer with dermatomyositis-polymyositis (DM-PM), but the relationship is uncertain. Patients may present with painful muscles and weakness. Blood tests for the muscle enzymes creatine kinase or aldolase will demonstrate elevated levels. An EMG or muscle biopsy is diagnostic. A CT scan of the chest is warranted in a patient with DM-PM who is at high risk for lung cancer. The treatment of patients with malignancy-related DM-PM is the same as for non malignancy related disease plus a propriate treatment of the underlying lung cancer.